The complex pathology of Alzheimer's disease includes various pathogenic components, such as metal-free amyloid-β (Aβ) and metal-bound Aβ (metal-Aβ). Here we report an effective strategy for developing novel heterocycle-fused 1,4-benzoquinone (BQ) compounds to control the aggregation and toxicity of both metal-free Aβ and metal-Aβ. We designed and synthesized these compounds by fusing BQ with 3-pyrazolone responsible for metal chelation. The compounds' ability to form covalent bonds with Aβ is tuned by the annulation of the BQ moiety and the type, position, and number of substituents on the 3-pyrazolone group. Furthermore, the BQ functionality on the 3-pyrazolone framework can undergo <i>o</i>-hydroxylation, enhancing its metal chelation in a bidentate manner. Our results demonstrate that these heterocycle-fused BQ compounds can redirect the assembly of Aβ into less toxic aggregates by binding to metal ions, modifying Aβ structures in both the absence and presence of metal ions, and promoting oxidative changes to Aβ. This study highlights the importance of structural modifications and optimizations of BQ to leverage its strength of covalently cross-linking to Aβ and overcome its limitations in metal chelation and cytotoxicity, which are critical for designing chemical modulators for metal-free Aβ and metal-Aβ. Our approach offers a novel strategy for developing chemical modulators towards metal-related peptides and proteins as well as therapeutic agents for metal-associated amyloid disorders.

Supercritical fluid extraction (SFE) with neat CO2 was optimized for selective removal of hyperforin and adhyperforin from St. John’s wort. High extraction efficiencies were achieved when the fluid density was 0.60 g ml−1 or above. The maximum extraction efficiency of hyperforin and adhyperforin could be achieved with a very mild condition such as 30 °C and 80 atm (density = 0.64 g ml−1). Under these conditions, the amount of hyperforin extracted was comparable to the results of conventional solvent-based extractions (ultrasonic or boiling). The maximum quantity of hyperforin extracted from the St. John’s wort was around 12 mg/g dry plant and the reproducibility of the SFE method was comparatively good (RSD = 10%). Hyperforin and adhyperforin were isolated from the crude SFE extract (using HPLC) with purities of 98.7 and 93.3%, respectively. The identity of the isolated hyperforins was confirmed by NMR and MS methods.

Nanometer-sized metallic palladium particles can be synthesized by hydrogen reduction of Pd2+ ions dissolved in the water core of a water-in-CO2 microemulsion. The Pd nanoparticles, stabilized by the micromeulsion and uniformly dispersed in the supercritical fluid phase, are effective catalysts for hydrogenation of olefins. Examples of rapid and efficient hydrogenation of water-soluble and CO2-soluble olefins catalyzed by the Pd nanoparticles in supercritical CO2 are given.

The complex pathology of Alzheimer's disease includes various pathogenic components, such as metal-free amyloid-β (Aβ) and metal-bound Aβ (metal-Aβ). Here we report an effective strategy for developing novel heterocycle-fused 1,4-benzoquinone (BQ) compounds to control the aggregation and toxicity of both metal-free Aβ and metal-Aβ. We designed and synthesized these compounds by fusing BQ with 3-pyrazolone responsible for metal chelation. The compounds' ability to form covalent bonds with Aβ is tuned by the annulation of the BQ moiety and the type, position, and number of substituents on the 3-pyrazolone group. Furthermore, the BQ functionality on the 3-pyrazolone framework can undergo <i>o</i>-hydroxylation, enhancing its metal chelation in a bidentate manner. Our results demonstrate that these heterocycle-fused BQ compounds can redirect the assembly of Aβ into less toxic aggregates by binding to metal ions, modifying Aβ structures in both the absence and presence of metal ions, and promoting oxidative changes to Aβ. This study highlights the importance of structural modifications and optimizations of BQ to leverage its strength of covalently cross-linking to Aβ and overcome its limitations in metal chelation and cytotoxicity, which are critical for designing chemical modulators for metal-free Aβ and metal-Aβ. Our approach offers a novel strategy for developing chemical modulators towards metal-related peptides and proteins as well as therapeutic agents for metal-associated amyloid disorders.

Supercritical fluid extraction (SFE) with neat CO2 was optimized for selective removal of hyperforin and adhyperforin from St. John’s wort. High extraction efficiencies were achieved when the fluid density was 0.60 g ml−1 or above. The maximum extraction efficiency of hyperforin and adhyperforin could be achieved with a very mild condition such as 30 °C and 80 atm (density = 0.64 g ml−1). Under these conditions, the amount of hyperforin extracted was comparable to the results of conventional solvent-based extractions (ultrasonic or boiling). The maximum quantity of hyperforin extracted from the St. John’s wort was around 12 mg/g dry plant and the reproducibility of the SFE method was comparatively good (RSD = 10%). Hyperforin and adhyperforin were isolated from the crude SFE extract (using HPLC) with purities of 98.7 and 93.3%, respectively. The identity of the isolated hyperforins was confirmed by NMR and MS methods.

Nanometer-sized metallic palladium particles can be synthesized by hydrogen reduction of Pd2+ ions dissolved in the water core of a water-in-CO2 microemulsion. The Pd nanoparticles, stabilized by the micromeulsion and uniformly dispersed in the supercritical fluid phase, are effective catalysts for hydrogenation of olefins. Examples of rapid and efficient hydrogenation of water-soluble and CO2-soluble olefins catalyzed by the Pd nanoparticles in supercritical CO2 are given.

Semiconductor nanopaparticles of CdS and ZnS were synthesized by mixing two water-in-CO2 microemulsions with one containing S2- ions and the other containing Cd2+ or Zn2+ ions in the water core. Nanoparticle formation was monitored in situ by measuring their absorption spectra in the UV−vis range using a high-pressure fiber-optic system. The size of the nanoparticles formed in the microemulsion was found to depend on the water-to-surfactant ratio (W). At W = 6 and 12, the band gaps of CdS were calculated to be 3.50 and 3.15 eV, corresponding to particle radii of 1.4 and 1.7 nm, respectively. The ZnS particles synthesized at W = 12 showed a band gap of 4.26 eV, corresponding to a mean particle radius of 1.6 nm. This microemulsion-plus-microemulsion approach offers a simple method for synthesizing various nanoparticles in supercritical CO2 using water-soluble reagents as starting materials.

ERK5 has emerged as a promising therapeutic target in cancer treatment due to its pivotal role in regulating tumor cell proliferation and survival. In this study, we synthesized novel derivatives of 1,4-dialkoxynaphthalene-2-acyl or 2-alkyl-imidazolium salt (NAIMS), assessed their binding affinity with the ERK5 protein through molecular modeling, and evaluated their anti-cancer activity through the ERK5 kinase assay. Based on the MTT assay and qRT-PCR analysis of 21 synthesized NAIMS, the IC₅₀ values for 4c, 4e, and 4k (8.5 μM, 6.8 μM, and 8.9 μM, respectively) and the inhibition rate of the expression of PCNA for 4c, 4e, and 4k (50%, 61.1%, and 70.2% of 5 μM respectively) were chosen for comprehensive biological research. Further analyses including DAPI staining, and flow cytometry confirmed that 4c, 4e, and 4k induced late-stage apoptosis, and triggered cell cycle arrest in the G2/M phase of HeLa cells. Moreover, molecular modeling analysis showed that 4e exhibited strong and stable molecular interactions at the ERK5 ATP-binding site. Our results strongly suggest that NAIMS compounds, especially 4e, could serve as novel inhibitors of ERK5, presenting promising lead compound to develop for cancer treatment.

ABSTRACT A series of novel 3‐alkoxypyrazole‐ and pyrazolone‐fused 1,4‐naphthoquinone derivatives were successfully synthesized through an intramolecular Ullmann‐type cyclization, using 1,4‐dihydroxy‐2‐naphthoic acid as the starting material. Subsequent regioselective N ‐ or O ‐alkylation followed by CAN‐mediated oxidation afforded the desired quinones in moderate to good yields. The molecular structures of the selected N ‐substituted derivatives were unambiguously confirmed by single‐crystal X‐ray diffraction. Preliminary cytotoxicity against RAW264.7 cells revealed that biological activity varied depending on the nature of substitution, with certain compounds exhibiting potent effects (LD 50 &lt; 5 μM). These findings highlight the potential of fused heterocycles as promising lead structures for anticancer drug development.